Exploration of Lamiaceae in Cardio Vascular Diseases and

Functional Foods: Medicine as Food and Food as Medicine

Ishani Chakrabartty, 1 , † Yugal Kishore Mohanta, 1 ,* † Amilia Nongbet, 2 , † Tapan Kumar
Mohanta, 3 ,* Saurov Mahanta,4 Nibedita Das, 2 Muthupandian
Saravanan, 5 and Nanaocha Sharma 6 ,*
Author information Article notes Copyright and License information Disclaimer

Associated Data
Supplementary Materials
2022; 13: 894814.
Published online 2022 Jun 14. doi: 10.3389/fphar.2022.894814
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Abstract

In the current scenario, cardiovascular disease (CVD) is one of the most

life-threatening diseases that has caused high mortality worldwide.
Several scientists, researchers, and doctors are now resorting to
medicinal plants and their metabolites for the treatment of different
diseases, including CVD. The present review focuses on one such family
of medicinal plants, called Lamiaceae, which has relieving and preventive
action on CVD. Lamiaceae has a cosmopolitan distribution and has great
importance in the traditional system of medicine. Lamiaceae members
exhibit a wide range of activities like antioxidant, antihyperlipidemic,
vasorelaxant, and thrombolytic effect, both in vitroand in vivo–these are
mechanisms that contribute to different aspects of CVD including stroke,
heart attack, and others. These plants harbour an array of bioactive
compounds like phenolic acids, flavonoids, alkaloids, and other
phytochemicals responsible for these actions. The review also highlights
that these plants are a rich source of essential nutrients and minerals like
omega-3 and hence, can serve as essential sources of functional foods—
this can have an additional role in the prevention of CVDs. However,
limitations still exist, and extensive research needs to be conducted on
the Lamiaceae family in the quest to develop new and effective plant-
based drugs and functional foods that can be used to treat and prevent
cardiovascular diseases worldwide.

Keywords: Lamiaceae, ethnopharmacology, CVD, functional food,

medicine
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1 Introduction

One of the fatal diseases today is cardiovascular disease or CVD. Such

diseases include a variety of disorders like stroke, heart failure,
myocardial infarction, and hypertension. According to the World Health
Organization (WHO), CVD accounts for 80% of death worldwide and is
the most rapidly increasing cause of death globally (Gaziano et al.,
2010; Rastogi et al., 2016; Chopra et al., 2022). All associated diseases of
CVD are characterized mainly by insufficient oxygen supply to the brain
and heart. This occurs due to excessive deposition of fats, lipids, and oils
in the cerebral and coronary arteries, which lead to the narrowing and
subsequent blockage of the pathway for blood flow (Roth et al., 2017).
Hypertension, the most common CVD today, has turned fatal due to fast-
paced lifestyles, stress, lack of adequate physical activity, and unhealthy
food habits (Shaito et al., 2020). Though many drugs like warfarin are
used to treat strokes and hemorrhage, they have not been able to lower
the death rate due to CVD (Lymperopoulos et al., 2013; Michel et al.,
2020). Under such conditions, scientists and chemists need to search for
and resort to other suitable alternatives; herbal medicines and plant
sources may serve as the possible safe option for treating this deadly
disease.

Food and lifestyle are very crucial today for the prevention of diseases
and to lead a healthy life. Functional or fortified foods and nutraceuticals
are gaining tremendous importance in this regard. According to
Healthline, those foods (with low trans-fat) that have health benefits
beyond their usual nutritional value, which are rich or fortified with
vitamins, minerals, fiber, probiotics, antioxidants, good quality fats,
secondary metabolites, and promote growth and development are called
functional foods (Linkr, 2020). Such foods can help modulate lipid
metabolism, which can prevent fat deposition and obesity; this further
contributes to minimizing the risk of CVD (Sikand et al., 2015). Foods
rich in secondary metabolites and bioactive compounds like flavonoids,
alkaloids, and others are recommended for consumption by dietary
guidelines to prevent stress, hypertension, and CVD (Jhonston,
2009; Rivera et al., 2010). Many families of plants like Asteraceae
(e.g., Artemisia campestris L.), Zingiberaceae (e.g., Alpinia galanga (L.)
Willd.), Caryophyllaceae (e.g., Corrigiola litoralis subsp. foliosa (Pérez
Lara) Devesa) and others are very rich in secondary metabolites and
have been consumed since time immemorial for their health benefits,
without the knowledge of nutraceuticals (Tungmunnithum et al.,
2018; Chakrabartty et al., 2020).

Plants form one of the essential footholds of modern drugs (Das et al.,
2015; Panda et al., 2019). For many years, traditional medicinal practices
like Ayurveda, Unani, and others have been based on plant-based
compounds; these practices are still religiously followed in some of the
secluded parts of India, China, and other developing nations as a
hierarchical legacy (Fabricant and Farnsworth, 2001; Panda et al., 2016).
Modern medical research often doubts the authenticity of traditional
methods; however, practitioners have not deterred from their path. Most
of them try to preserve such age-old knowledge within families. Hence
minimal literature or documentation can be found. It is interesting to
note that according to WHO, more than 80% of the global population still
rely on traditional and herbal medicines, even for life-threatening
diseases. Most medicinal plants have the added advantage that they are
consumed worldwide as foods. For many years, different species from
the Zingiberaceae family are used as traditional medicines as home
remedies for the treatment of certain diseases in Southeast Asian
countries like India, like decoction of Alpinia nigra (Gaertn.) Burtt to
treat gut infection by Fasciolis, Curcuma sp. for wound
healing, Zingiber sp. for viral infections etc. (Kunnumakkara et al.,
2008; Roy et al., 2012; Swargiary et al., 2013; Chakrabartty et al., 2019).
Another such family is Lamiaceae, which is very rich in medicinal plants
and has long been used as traditional medicine.

Lamiaceae, or mint family, is a widely distributed family of angiosperms

that consists of 236 genera with more than 7,000 species (Michel et al.,
2020). The largest genera that belong to this family are Salvia,
Scutellaria, Stachys, Ajuga, Plectranthus, Hyptis, Teucrium, Vitex, Thymus,
Nepeta, etc. The different species from this family inhabit diverse
ecosystems and have a great diversity with a cosmopolitan distribution.
Members of plants this family are important in various industries like
perfumery, pharmaceutics, cosmetics, food, fragrance, and others. Such
diverse applications lead to the widespread cultivation of the plants of
Lamiaceae are, therefore, grown to serve as sources of functional food
(Hyde et al., 2014; Li et al., 2016; Zhao et al., 2021). In addition, a number
of these plants are aromatic, which can be attributed to a wide variety of
complex bioactive compounds that further possess high biological
activity both in vitro and in vivo. Secondary metabolites that show a high
amount of potential, like antioxidant, antimicrobial, and anticancer
effects, and are vital for their biological efficacy; hence, plants of
Lamiaceae play an important role in the treatment of many diseases,
including CVD (Stevens, 2012).

The present review aims at bridging the gap in existing literature

regarding the role of several members of the family Lamiaceae,
particularly in the prevention of CVD and their application as functional
foods. Further, it is sub-divided into different sections: Section
2 describes the importance of “mint,” the representative term for
Lamiaceae and how it is searched for globally. The following section
(Section 3) highlights the role of the Lamiaceae family in the prevention
and cure of CVD and its associated diseases. In Section 4, the different
bioactive compounds from other species of Lamiaceae are described that
have a preventive role in CVD. In Section 5, the role of Lamiaceae as
functional foods has been discussed in detail. The challenges and
opportunities to utilize the plants of the Lamiaceae family as medicines
and nutraceuticals have also been discussed in the subsequent portion
(Section 6). In Section 7, the prospects of research in Lamiaceae (in
search of novel bioactive compounds to be used as medicines and
fortified foods) and the concluding remarks on the present study have
been discussed.

Most of the information provided in this manuscript has been collected

from freely available journal articles, book chapters, monographs, online
articles, etc. that are cited in the text. Electronic databases like Google
Scholar, Library Genesis, and Sci-Hub have been used for the data
collection. The presently accepted nomenclature of the plants has been
used throughout the text and checked for validity. Most of the data
referred to here, include the latest and updated information between
2010 and 2022; however, some old data from 2003 to 2009 have also
been referred and used because of the relevant information.
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2 World-Wide Ethnopharmacological Exploration of Lamiaceae

Mint, the refreshing flavour loved by people globally, is associated with
the Lamiaceae family. Several people search about mint and its usage in
Google to know about it. Google records these search terms and provides
a comprehensive idea about the trend of search terms. Therefore, we
searched for Google trends (from January 2004 to February 2022) to
understand people’s opinions towards the mint and its flavour. Our
search criteria ranged Google trend results revealed that the term “mint”
was searched for the highest number of times in December 2021 and the
lowest in September 2008 (Supplementary Material S1). The global
search for the term “mint” is continuously increasing with a substantial
increase in the blue colour’s depth is mentioned in the specific territory
of different parts of the world (Figure 1). However, in February 2022, it
witnessed a downward trend. If country-specific search trends are
considered, the people of Brazil have the highest interest in the search
term mint followed by Portugal, the United States, and the United
Kingdom (Supplementary Material S2).
FIGURE 1
Worldwide exploration of Lamiaceae for ethnopharmacological evaluations and other use.
(Figure Source: The Authors and the figure is made using ArcGIS Pro software).

In contrast, France showed the lowest data in terms of search results.

However, at least 205 countries/regions of the globe have little or no
interest in mint (Supplementary Material S2). This shows that most of
the global population still does not have an interest in mint; it is
concentrated in only 45 countries. Though some countries might have
searched for mint in Google trends, their search was not enough to make
a considerable impact recorded in Google compared to Brazil. Mint is a
representative member of Lamiaceae and hence, the term “mint” is
believed to represent the entire family. This plant has a characteristic
property related to a cooling and stimulating effect in the breath and,
later, the entire body. Brazil is a tropical nation that records very high
temperatures. This may be one of the probable reasons why the search
term “mint” is very commonly googled by the people of this country
compared to the cold European nation of France.
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3 Activity of Lamiaceae in CVD

A lot of plant species, belonging to different families like Zingiberaceae,
Asteraceae, and others, are explored presently that have a wide range of
activities like analgesic, anti-inflammatory, antioxidant, vasodilating
properties, etc.—many of which can help to prevent CVD (De Souza et al.,
2013; Basak et al., 2018; Chakrabartty et al., 2019; Michel et al., 2020).
The subsequent sections discuss in detail how different species of
Lamiaceae contribute to the prevention of CVD (Table 1, Figure 2); their
toxicity profile has also been highlighted (Supplementary Table S1).
TABLE 1
Mechanism of action of plants from Lamiaceae in the prevention of CVD.

Plant
Sr. Mechanism of
Plant name organ/Extract References
No. action
type
Reduced blood
The whole plant plasma cholesterol
Taleb-Senouci et
1. Ajuga iva (L.) Schreb. (Aqueous and triglyceride
al. (2009)
extract) levels; lowered
lipid peroxidation
Caused significant
diuresis; aqueous
Leaves extract showed Hailu and
Ajuga integrifolia Buch. -
2. (methanolic diuresis at high Engidawork,
Ham. ex D. Don
extract) conc. after 5th (2014)
hour of
administration
Aerial parts Lowered the blood
(Crude and pressure and
3. Clinopodium vulgare L. Khan et al. (2018)
methanolic hypertension (10–
extract) 30 mg kg−1)
Fraction exhibited
Aerial parts (As high antioxidant
Dracocephalum
4. food or and free radical Jiang et al. (2014)
moldavica L.
decoction) scavenging activity
(>70 mg L−1)
Exhibited very
high antioxidant
Aerial parts
activity Ez Zoubi et al.
5. Lavandula stoechas L. (Ethanolic
(12 μg ml ); value (2014)
−1
extract)
comparable to
BHT
 Plant
Sr. Mechanism of
Plant name organ/Extract References
No. action
type
Acted on voltage-
gated K+channels,
The whole plant mobilized Ca2+ions
Ziziphora Senejoux et al.
6. (Decoction of and caused
clinopodioidesLam. (2010)
whole plant) relaxation of
vascular smooth
muscles
Caused
vasorelaxation
effect on
endothelium-aortic
The whole plant Yam et al.
Orthosiphon rings and
7. (Aqueous (2016), Yam et al.
aristatus(Blume) Miq. porphyrin rings by
extract) (2018)
KCl induced
mechanism using
NO/cGC/cGMP
pathways
Lowered plasma
cholesterol (500–
1,000 mg kg−1) and
Vitex Leaves
LDL level;
8. megapotamica(Spreng.) (Aqueous Pires et al. (2018)
prevented
Moldenke extract)
formation of
atherosclerotic
plaques
Inhibited lipid
Dorman et al.
peroxidation; had
Shoots (Crude (2003), Hossain
high antioxidant
9. Salvia officinalis L. material, et al.
property by
essential oils) (2010), Michel
scavenging free
et al. (2020)
radicals of oxygen
Significantly
lowered plasma
The whole plant levels of Ramchoun et al.
10. Thymus saturejoides Coss. (extract type triglycerides (conc. (2012), Khouya
unknown) 0.2 g 100g−1) and et al. (2015)
cholesterol, along
with LDL levels
Salvia Roots (Oral Inhibited platelet
11. miltiorrhiza Bunge Salvia consumption of aggregation in the Fan et al. (2010)
miltiorrhiza var. dried root) blood and reduced
 Plant
Sr. Mechanism of
Plant name organ/Extract References
No. action
type
charbonnelii (H.Lév.) weight of
C.Y.Wu thrombus (clot)
Significantly
Aerial parts lowered heart rate
(Methanolic and blood
Lepechinia Estrada-Soto et
12. extract; pressure; had
caulescens(Ortega) Epling al. (2012)
decoction or vasorelaxation
tea) effect (conc. 30
and 120 mg kg−1)
Increased HDL
concentration in
the blood;
The whole plant
exhibited free Zargar et al.
(Hydroacoholic
13. Prunella vulgaris L. radical scavenging (2017), Michel
and aqueous
activity on et al. (2020)
extract)
superoxide and
hydrogen
peroxide.
Caused relaxation
of contracted
Leaves
Pogostemon aortic rings in a Shiva Kumar et
14. (Essential oil;
elsholtzioidesBenth. dose-dependent al. (2017)
leaf decoction)
manner and
lowered heart rate
Lowered serum
Leaves levels of Vijay Kumar
Leucas aspera (Willd.)
15. (Ethanolic cholesterol and and Devanna,
Link
extract) triglycerides (conc. (2016)
100–200 mg kg−1)
Reduced pressure
on the ventricles
and eased flow of
Aerial parts
blood through
(Refined extract Ritter et al.
16. Leonurus cardiaca L. coronary arteries
given as (2010)
in a dose-
infusion)
dependent manner
(conc. 1–
2 mg ml−1)
Aerial parts Decreased blood
Sideritis raeseri Boiss. & Kitic et al.
17. (Extract type pressure and heart
Heldr. (2012)
unknown) rate in a dose-
 Plant
Sr. Mechanism of
Plant name organ/Extract References
No. action
type
dependent manner,
and led to
vasodilation
Inhibited KCl and
adrenaline-induced
The whole plant contraction of Ramón Sánchez
Satureja cuneifolia Ten.
18. (Aqueous smooth muscles at de Rojas et al.
(syn.
extract) toric phase in a (1999)
concentration-
dependent manner
Lowered levels of
cholesterol and
Aerial parts triglycerides in the Michel et al.
19. Teucrium polium L. (Aqueous blood in a dose- (2020), Rasekh
extract) dependent manner; et al. (2001)
exhibited diuretic
effect
Open in a separate window
aAll the scientific names of the plants are mentioned in the table according to version 1.1 of
the Plant List Published on the Internet (The Plant List, 2013)
and http://mpns.kew.org/mpns-portal/.
FIGURE 2
Exploration of Lamiaceae bioactive natural products on CVD (Figure Made
in BioRender.com).

3.1 Antioxidant Activity

Antioxidants are those chemical substances that can negate the harmful
effects of free radicals and hence prevent the tissues from getting
damaged. As such, they help safeguard against CVD (Michel et al., 2020).
The generation of reactive oxidative species (ROS) can lead to oxidative
stress and attack the vital biomolecules of the body, leading to damage to
endothelial cells and vascular tissues. This can also lead to
atherosclerosis and the conditions may become fatal over time (Taleb et
al., 2018). It has been reported that natural antioxidants, especially from
plant sources, have a tremendous potential for scavenging free radicals,
chelating metal ions, enhancing the endogenous antioxidant system, and
further preventing the formation of reactive species (Supplementary
Table S3); hence, there are an intense and aggressive search plant-based
antioxidants (Amic et al., 2003; Seyoum et al., 2006). Common bioactive
drugs of Lamiaceae like oregano (Origanum vulgaris L.), rosemary
(Rosemarinus officinalis L.), basil (Ocimum basilicum L.), thyme (Thymus
vulgaris L.), and sage (Salvia officinalis L.) possess high antioxidant
properties; they are reported to have free radical scavenging activity
which increases upon heat exposure and drying (Hossain et al., 2010).
Medicinal plants of Lamiaceae, Lycopus europaeus L., Melissa officinalis L.,
and Prunella vulgaris L. have shown significant anti-oxidative activities
by free radical scavenger effect on DPPH (SC50 values ranging from 16.7 ±
1.1 to 221.8 ± 49.0 µΜ for the three plants), which have been reported to
be higher than that of rosmarinic acid (SC50: 5.5 ± 0.2 µM) (Michel et al.,
2020). Thymus sipyleus Boiss. subsp. sipyleus var. sipyleus, Teucrium
chamaedrys L., Mentha longifolia (L.) Hudson subsp. longifolia, Salvia
limbata C.A. Meyer, and Thymus fallax Fisch. and Mey, are very rich in
phenols and flavonoids—these impart antioxidant properties to the
extracts of the plants which are capable of regenerating antioxidant
properties in the lipid bilayer of cells (Özgen et al., 2006). Firuzi et al.
(2010) estimated the antioxidant activity of 24 species of Lamiaceae
from Iran that included plants like Ballota aucheri Boiss., Eremostachys
adenantha Jaub. & Spach Ill, Otostegia michauxii Briq., Phlomis
ellipticaBenth., Phlomis olivieri Benth., Phlomis persica Benth., Thymus
daenensis Celak., and nine species of Salvia by DPPH and FRAP assay—of
these, Salvia santolinifolia Boiss. has the highest antioxidant activity,
comparable to the positive control, ascorbic acid (Firuzi et al.,
2010; Michel et al., 2020). The essential oils were obtained from the
aerial parts of Lavandula angustifolia Mill. and Lavandula stoechas L. also
show high antioxidant activity (Ziaee et al., 2015). In addition, the
ethanolic extract of the leaves of sage contains a high amount of phenolic
acids, which exhibit high antioxidant activity as the phenol ring can
easily give up H2 atoms (Ramu et al., 2012).

3.2 Blood Cholesterol and Lipid-Lowering Activity

An increase in blood cholesterol and triglycerides are another cause of
CVD. It can lead to atherosclerosis—the condition in which fat droplets
and lipids get deposited and hardened in the arteries obstructing the free
flow of blood. This leads to various cardiac and coronary diseases like
stroke and vascular diseases. The ability of substances to break down
these hardened fat depositions is called the antihyperlipidemic or
hypolipidemic effect, which can lower the level of triglycerides like low-
density lipoprotein (LDL) and cholesterol and help to increase the “good”
high-density lipoprotein (HDL) (Akinpelu et al., 2016). Thus, they can
alleviate the risk of CVD greatly. The extracts obtained from the different
plant organs of Lamiaceae are very rich in polyphenols and exhibit an
antihyperlipidemic effect. The dried hydroalcoholic
extract Dracocephalum kotschyi Boiss (dosage 40 mg kg−1 body weight)
has been reported as the best dose for hyperlipidemia in rats and can
significantly reduce the risk of atherosclerosis (Heydari et al., 2019). The
ethanolic and ether extracts of Leucas aspera, which are used in folklore
to treat various ailments, are rich in secondary metabolites. The steroidal
phytochemicals tend to replace cholesterol in triglyceride formation that
further leading to a hypolipidemic effect; the extract was effective in a
dose-dependent manner in rat modes with induced hyperlipidemia
(dexamethasone treatment) (Vijay Kumar and Devanna, 2016). Indian
tulsi (Ocimum tenuiflorum L.) is traditionally used as an anti-tussive
agent. The alcoholic extract of this plant has a no. of phenolic
compounds—each of which has anti-hyperlipidemic activity. In addition,
the extract (125–500 mg kg−1 body weight) can lower the level of LDL
and increase HDL up to the story of a healthy rat (Parasuraman et al.,
2015). Aqueous extracts of Thymus saturejoides Coss. (0.2 g per 100 g of
extract) can significantly lower blood plasma cholesterol and triglyceride
levels—this decrease is associated with the reduction of LDL levels.
Similarly, the aqueous extract of Teucrium polium L. (50–150 mg kg−1 of
extract) can decrease levels of cholesterol and triglycerides in the blood
of hyperlipidemic rats in a dose-dependent manner (Khouya et al.,
2015).

3.3 Anticoagulation and Thrombolytic Activity

Blood clotting involves a complex series of events—the breakdown to
protein activates the process of thrombin formation that further
converts fibrinogen to fibrin. Factor VIII with platelets triggers this set of
circumstances and aid in the process of blood clotting or blood
coagulation. The formation of a thrombus or clot in the arteries and
tissues is prevented by anticoagulants (Schaeffer and Zimlich, 2019).
Few plants of Lamiaceae have been reported to possess anticoagulation
potential. Ali et al. (2014) revealed thrombolytic activity of methanol
extract and solvent fractions (petroleum ether, chloroform, carbon
tetrachloride) and aqueous fractions of the leaves of Clerodendrum
infortunatum L. by clot lysis assay; the carbon tetrachloride and
chloroform fractions displayed the highest and least percentage of clot
lysis. The different bits of the root extract of this plant also showed
thrombolytic activity (Ali et al., 2014; Prashith Kekuda et al., 2019). The
leaf extracts of Salvia officinalis L., Thymus vulgaris L. and Rosmarinus
officinalis L. (200–1,000 μg ml−1) exhibit thrombolytic activity in a dose-
dependent manner; their thrombolytic potential can be arranged in the
order Salvia officinalis L. > Thymus vulgaris L. > Rosmarinus officinalis L.
(Mutalib, 2015). In addition, Salvia miltiorrhiza (Bunge) also exhibited
mild inhibition of platelet aggregation in vivo in rats. Another member of
Lamiaceae, Leonotis leonurus (L.) R. showed anticoagulation potential
both in vitro and in vivo. The plant extract lowered or prevented the
expression of proteins responsible for platelet aggregation and blood
clotting. At a concentration of 50–100 μg ml−1, platelet adhesion was
reduced in a dose-dependent manner, and preventing activation of
thrombin and fibrinogen (Mnonopi et al., 2011).

3.4 Inhibitory Action on Hypertension

Excessive contraction of blood vessels for a prolonged duration causes

an increase in blood pressure, leading to hypertension. Vasorelaxants are
drugs that can cause dilation of blood vessels that ensure the flow of
blood through the vessels at ease—most of these cause relaxation of
vascular smooth muscles—the most common method of treatment used
for hypertension (Herradón et al., 2007). It has been reported that plant-
based compounds like chalcones inhibit angiotensin-converting exam
(ACE) through nitric oxide (NO)- and estrogen receptor α (ERα)-
dependent pathways to bring about vasorelaxation and lower the risk of
CVDs (Legeay et al., 2020). Agastache mexicana (Kunth.) Lint. and Epling,
is a medicinal plant from the Lamiaceae family used for the treatment of
anxiety. The antihypertensive activity of the plant extract was
determined in the male rat - the extract exhibited relaxant activity and
exhibited vasodilation effect through several receptors, such as the
augment of free cytosolic Ca2+ levels; it further inhibited vasoconstriction
and showed a diuretic effect, preventing hypertension (Hernandez-
Abreu et al., 2013; Flores-flores et al., 2016). Senejoux et al.
(2010) reported the vasodilation activity of Ziziphora
clinopodioides Lam., a plant that finds its use in Chinese folk medicine for
the treatment of hypertension. The decoctions of the whole plant of Z.
clinopodioides decreased the influx of Ca2+ ions in KCl mediated
contractions of vascular smooth muscles. Further, the vasorelaxation of
this extract did not involve endothelium-derived relaxing factors like NO
and prostacyclin (Senejoux et al., 2010). The sections of Clinopodium
vulgare L., another member of the mint family, have vasodilation
potential in rats both in vitro and in vivo. At a concentration of 1–
30 mg kg−1, the vasorelaxation in rat aorta was endothelium
mediated, i.e. it involves muscular NO channels, K+ channels, together
with the closure of Ca2+ ion channels, and occurred in a dose-dependent
manner (Khan et al., 2018). The extract of Orthosiphon aristatus (Blume)
Miq. Possesses vasorelaxation or vasodilation activity, which exhibited a
relaxation on KCl-induced aortic rings of the endothelium and
phenylephrine-induced aortic ring that may or may not have
endothelium in rats; pathways that are involved in this vasorelaxant
activity are NO/sGC/cGMP pathways (Yam et al., 2016, 2018). Other
members of Lamiaceae that are engaged in vasorelaxation and
vasodilation are Melissa officinalis L., Orthosiphon aristatus (Blume) Miq.
(syn. Orthosiphon stamineus Benth.), Phlomoides bracteosa (Royle ex
Benth.) Kamelin and Makhm., Plectranthus hadiensis (Forssk.) Schweinf.
ex Sprenger (syn. Coleus forskohliiWilld.), Pogostemon
elsholtzioides Benth, Satureja cuneifolia Ten. (syn. Satureja
obovata Lag.), Sideritis raeseri Boiss. and Heldr (Michel et al., 2020).

3.5 Diuretic Activity

Drugs that aid in diuresis can increase the urinary volume; this can lower
the risk of heart disorders and ease out conditions like heart failure,
pulmonary oedema, and stroke. Many drugs are available that can be
used alone or in combination for diuresis, but they have a myriad of
adverse effects with them. Research on plants and plant-based bioactive
compounds suggests that plant species exhibit diuretic activity with
negligible side effects; some plants of the Lamiaceae family have been
reported for the same (Gupta and Neyses, 2005; Morganti, 2005; Michel
et al., 2020). The different solvent extracts (aqueous, alcoholic and ethyl
acetate) of the leaf of Plectranthus amboinicus (Lour) Spreng increases
urine volume and decreases serum Na level of albino rats in comparison
to the available drug but had no effect on the serum K level; the ethyl
acetate fraction was more potent as a diuretic group with better
electrolyte balance than the other solvent fractions (El-Hawary et al.,
2012). The aqueous and ethanol extracts of Coleus amboinicus, Lour. Has
also shown significant diuretic activity (Venkateshappa and Sreenath,
2013). Ajuga integrifolia Buch. -Ham. ex D. Don) is a perennial
herbaceous plant of Lamiaceae that has significant diuretic activity; its
aqueous and 80% methanolic extract showed an increase in urine
volume and the diuretic effect, together with electrolyte excretion effect,
was comparable to that produced by diuretic drug furosemide (Hailu and
Engidawork, 2014). Clerodendrum myricoides Hoscht. has been used as a
traditional medicine for curing various ailments like urine retention and
oedema. This plant’s hydromethanolic leaf and root extracts and its
fractions (ethyl acetate, chloroform, and alcohol) showed diuretic
activity in rats in vivo—the hydromethanolic extract showed higher
diuresis than furosemide (100 mg kg−1). It is reported that this extract
had higher solubility for pharmacologically active ingredients like
flavonoids, tannins, terpenes, phenols, saponins and others, and they also
act synergistically; moreover, this extract has very minimal cell
cytotoxicity (Welu et al., 2020). Other plants from Lamiaceae that show
diuretic activity are Anisomeles indica L., Teucrium polium L., and Ajuga
integrifolia Buch. -Ham. ex D. Don (Malki and Yahia, 2014).
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4 Bioactive Compounds From Lamiaceae and Their Role in CVD

According to the National Cancer Institute (NCI) dictionary, a bioactive
compound is a chemical compound that is present in minimal amounts in
living systems like plants and microorganisms, and even foods like nuts
and cereals. These compounds have benefits to human health like
promoting growth, antimicrobial potential, and prevention of diseases
like cancer and CVD
(https://www.cancer.gov/publications/dictionaries/cancer-
terms/def/bioactive-compound). Most families of plants like
Euphorbiaceae, Zingiberaceae, Asteraceae, and others possess a large no.
of bioactive compounds that have different medicinal properties and
mainly include secondary plant metabolites like flavonoids, terpenoids,
chalcones, alkaloids, saponins, tannins etc. It is important to note that the
quantity of bioactive compounds produced by any plant has a powerful
influence on the environment. For instance, the essential oil content from
the leaves of Alpinia nigra (Gaertn.) Burtt is slightly higher in Assam than
in Bangladesh. The climate, temperature, soil, harvest time, other
ecological factors, and the mode of oil extraction used, may influence the
oil yield (Ghosh et al., 2013; Islam et al., 2014).

Many plants of Lamiaceae like Micromeria

macrosiphon Coss., Plectranthus monostachyus (P. Beauv.) B.J.
Pollard, Ballota glandulosissima Hub. -Mor. & Patzak, Lallemantia
royleana (Benth.) Benth., Thymus dreatensis Batt. and many others play
an important role in preventing CVD and its associated disorders; such
potential is also imparted to the plant by the presence of
pharmacologically functional elements or bioactive compounds present
in the different plant parts at varying concentrations (Table 2). A number
these compounds can be derived as potential lead drugs for the
treatment of CVDs (Figure 3); their mechanism of action has also been
provided (Figure 4; Table 2). These compounds have been isolated
primarily by column chromatography and characterized extensively
using several analytical techniques like preparative Thin Layer
Chromatography (pTLC), High-Performance Liquid Chromatography
(HPLC), Ultraviolet (UV) spectral analysis, Fourier Transform Infrared
Spectroscopy (FTIR), 13C and 1H Nuclear Magnetic Resonance (NMR)
and Mass Spectroscopy (MS) (Ghosh and Rangan, 2013; Chakrabartty et
al., 2018). The clinical trial data of these compounds have also been
included (Supplementary Table S2). A bioactive compound, marrubiin,
isolated from Leonotis leonurus (L.) R. Br. can prevent platelet
aggregation and lyse thrombus both in vitro and in vivo. This diterpenoid
also lowers insulin secretion, LDL and blood cholesterol, IL-1β and IL-6
levels, and increases HDL concentration (Mnonopi et al., 2011; Mazimba,
2015). Indian tulsi has a number of bioactive compounds like eugenol,
rosmarinic acid, carvacrol, linalool, estragole, caryophyllene, ursolic acid,
apigenin, and cirsimaritin, which have antihyperlipidemic activity
(Pattanayak et al., 2010; Jamshidi and Cohen, 2017). Origanum vulgare L.
or Oregano is rich in phenolic compounds with very high antioxidant
activity. These phenolic compounds are apigenin, luteolin, rosmarinic
acid, 2,5-dihydroxybezoic acid, 3,4-dihydrobezoic acid, caffeic acid,
maltol, quercetin, scutellarin and others; most of them have associated
biological activities like antiviral, antimicrobial, anti-plasmodial,
anticancer etc. It is reported that the phenolic structure of these
compounds is responsible for the free radical scavenging activity (Zhang
et al., 2014; Gutiérrez-Grijalva et al., 2018). Similarly, the ethanolic
extracts of sage (Salvia officinalis L.) is rich in flavonoids and phenols like
cirsimaritin, apigenin, epirosmanol, hespertin, carnosol; the high
antioxidant activity is due to the presence of vast amounts of rosmarinic
acid and chlorogenic acid which can donate H-atoms to the free radicals
(Generalić et al., 2012; Ramu et al., 2012). Sinensetin (0.262 μg ml−1) and
eupatorin, bioactive compounds from Orthosiphon aristatus (Blume) Miq.
have vasorelaxant activity that utilizes the NO/cGC/cGMP pathways. In
addition, they have anticancer solid potential and other pharmacological
properties, with minimal or no toxicity to the target tissues (Yam et al.,
2018; Han Jie et al., 2021). The methanolic extract of purple Himalayan
mint or Phlomoides bracteosa (Royle ex Benth.) Kamelin & Makhm.
contains two compounds marrubiin and phlomeoic acid, which have
vasorelaxation properties—marrubiin can block the voltage-gated
channel of Ca2+ ions and inhibit K+ ion mediated contraction of the aortic
rings (Khan et al., 2012). Salvianolic acid is an active component
obtained from Salvia miltiorrhiza (Bunge) that has thrombolytic activity
at a concentration of 2–10 mg kg−1 in a dose-dependent manner; the
compound prevents platelet aggregation by binding with thrombin and,
thus, interferes with the clotting signaling pathway (Fan et al.,
2010; Michel et al., 2020). Therefore, the Lamiaceae members include a
vast number of active ingredients that have a direct or direct role in
preventing CVD.

5 Lamiaceae as Functional Foods

Lamiaceae is an essential group of medicinal plants, comprising mainly

aromatic plants containing compounds such as flavonoids, terpenes,
phenolic compounds, polyphenols, iridoids, and many other active
compounds. The number of Lamiaceae plants used in essential oil
production is more than 30 species worldwide that are used as food or
food additives to prevent the risk of cardiovascular diseases, cancer, and
diabetes. Effective use of Lamiaceae plants is underway to develop new
natural products that can help the patients prevent and treat many
cardiovascular and other related diseases. Cardiovascular diseases
(CVDs) are disorders of the heart and blood vessels with coronary heart
disease, heart failure, hypertension, hyperlipidaemia, and
thromboembolism. The estimated mortality rate from CVDs as per the
World Health Organization (WHO) is 32% of all global deaths. It is
expected to reach 23.3 million before 2030 (Suroowan and
Mahomoodally, 2015). Medicinal plants have been traditionally used
from time immemorial to treat many diseases, including CVDs and
related complications. Many of the commercially available drugs for the
treatment of CVDs are derived from herbal plants. Lamiaceae family has
potent cardioprotective effects as reported by many studies on medicinal
and aromatic bioactive drugs (Patrignani et al., 2021). The plants are
either used as crude extracts, essential oils (Eos), or by extraction of the
active compounds against CVD. The active compounds extracted from
this plant family have been reported as promising cardioprotective
activity in vitro and in vivo (Table 3).

Effects of Lamiaceae Functional Food Components as

Cardioprotective
Plants of Lamiaceae possess promising benefits in reducing the risk of
CVDs through the suppression of inflammation (Tzima et al., 2018). The
methanolic extract of Satureja hortensis L. plant is well known for CVDs
treatment and other related complications by inhibiting the secretion,
aggregation and adhesion of the blood platelet and the anticoagulant
activity blood (Hamidpour et al., 2014). The leaf extract of Ocimum
basilicum L. showed an anticoagulant effect, as reported by Pour et al.
(2016) (Pour et al., 2016). The Lavandula aguistifolia Mill. contain
bioactive compounds such as flavonoids, tannins, triterpenoids,
coumarins, cineole, limonene, and camphor showed substantial
antioxidant properties with reduced cardiac tissue damage and
strengthened myocardial membrane (Koshma et al., 2018). The plant
extract of Leonotis leonurus (L.) R.Br.contains a primary compound
named Marrubiin (labdane diterpenoid) exhibiting antiplatelet,
anticoagulant, and anti-inflammatory properties (Mnonopi et al., 2011).
The Leonurus turkestanicusV.I.Krecz. & Kuprian. as reported by
(Mamadalieva et al., 2017), shown to be effective against cardiovascular,
stomach, and other related diseases. As shown by histopathological
analysis, Stachys schimperi Vatke possesses cardioprotective effects on
DOX-induced cardiotoxicity in rats. Rosmarinic acid found in basil leaves
(Ocimum basilicum L.) exhibited cardioprotective effects in rats with
isoproterenol-induced myocardial infarction (Koshma et al., 2018). One
of the major components found in most species of the Lamiaceae family,
Thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) showed
healing effects against apoptosis, coronary artery diseases, diabetes,
urinary system failures, hypertension, inflammation, and oxidative stress
which is related to its antioxidant and anti-inflammatory activity
(Farkhondeh et al., 2017). Components such as methylripariochromene
A, orthochromene A, neoorthosiphol A and B and tetramethylscutell
isolated from the leaves of Orthosiphon species of Lamiaceae family have
been studied and showed decreased systolic blood pressure (Singh et al.,
2015). Essential oil of Lavandula angustifolia Mill. has been shown to
protect isoproterenol-induced myocardial infarction in a study using rat
antioxidant activity (Ziaee et al., 2015) (Table 3).
Incorporating bioactive drugs from the Lamiaceae family (sage, mint,
rosemary, oregano, thyme) into the innovative functional foods on
aroma compound formation and sensory properties oat-buckwheat
products. Herbs of Lamiaceae contain a unique, complex mixture of
bioactive compounds. They include secondary metabolites such as
phenolic compounds, tannins, quinines, lignans, terpenoids, and
flavonoids and they are also rich in essential oils and can enhance the
taste and aroma of the final product (Vaishali Rai et al., 2013; Carović-
Stanko et al., 2016; El-Sayed and Youssef, 2019). Most herbs and spices
have relatively high micronutrients (minerals and vitamins),
macronutrients (such as protein, fat, and carbohydrate) and fewer anti-
nutritional properties. The total antioxidant potential of plant materials
such as culinary herbs, spices, vegetables, as well as fruits and oilseed
products are related to ascorbic acid (vitamin C), alpha-tocopherol
(Vitamin E), beta-carotene (Vitamin A precursor), numerous flavonoids,
and other phenolic compounds (Rather et al., 2016). Basil (Ocimum
basilicum L.) is one of the most popular cultivated plants. It is a good
source of natural antioxidants and contains significant amounts of
essential phytochemicals. The inclusion of basil in the development of
fresh cheese made with organic buffalo milk did not modify the fat,
protein, moisture, and mineral content. In contrast, the total polyphenol
content and antioxidant activity of cheeses increased. It also changed the
hardened and chewiness but not influenced springiness and
cohesiveness. Thus, the basil improves the functional and modified
technological characteristics of fresh cheeses and presents good
acceptability (Ribas et al., 2019). Food can be functional by increasing
concentration, adding or improving the bioavailability of bioactive
ingredients, such as probiotics, fibres, phytochemicals, vitamins,
minerals, bioactive drugs, omega-3s, peptides-proteins (Roberfroid,
2002; Arvanitoyannis and Van Houwelingen-Koukaliaroglou, 2005).
Basil (Ocimum basilicum L.) is rich in polyphenols, antioxidant,
antimicrobial and antifungal properties (Carocho et al., 2016). The basil
branches mainly contain fibers, essential oils and minerals, such as
nitrogen, calcium, potassium and magnesium. Basil leaves have
significant amounts of carotene, vitamin B (1, 2, 3), vitamin C, minerals
(calcium, phosphorus and iron), polyphenols and essential oils
(Dumbrava et al., 2012). Thus, it can be added to foods as a functional
ingredient, such as dairy products. Phenolic compounds, secondary
outcomes of plant metabolism, have been suggested as bioactive
compounds due to their antioxidant capacity and beneficial effects on
human health (Han et al., 2011). Additions of seasoning plants, rich in
phenolic compounds, in cheeses have already been reported (Asensio et
al., 2015).

5.2 Active Food Components With Cardiovascular Effect

Some of the bioactive compounds from the Lamiaceae plant family with
cardio-protective and therapeutic properties include leonurine,
rosmarinic acid, quercetin, apigenin, carvacrol, thymoquinone, baicalein,
and many others (Table 3). The cardioprotective effects exhibited by
these compounds are through multiple regulations, including growth
factors, enzymes, kinases, apoptotic, transcription factors, and other
molecules.

Apigenin has shown similar mechanisms in cardio-protection by

inhibiting the phosphorylation of p38 MAPKS during myocardial I/R and
reducing the activity of caspase-3 activity and Bax protein expression
while the expression of Bcl-2 protein is increased (Hu et al., 2015; Chen
Y. et al., 2017). Leonurine, a natural active compound of Leonurus
cardiaca L. acts as an adjuvant cardioprotective agent and has anti-
oxidative and anti-apoptotic properties (Liu et al., 2009, 2010) and also
increases the hypoxia-inducible factor-1α (HIF-1α) in H9c2 cardiac
myocytes expression and Akt phosphorylation (Liu et al., 2010) leading
to suppression of cardiac cell death. Moreover, leonurine exerts potent
cardioprotective effects by either increasing the level of p-PIK, p-AAKT,
p-GSK3ß and Bcl-2, or decreasing the levels of caspase 3, cleaved-
caspase3 and Bax (Xu et al., 2018). Rosmarinic acid displays effective
cardioprotective effects by increasing the enzymes involved in
antioxidant activity and regulating the sarcoplasmic reticulum
Ca2+ homeostasis gene expression (Javidanpour et al., 2017). It also
protects against cardiac fibrosis by inhibiting phosphorylation, activating
the AMPKα, and nuclear translocation of Smad3 and attenuating cardiac
fibrosis by inducing peroxisome proliferator-activated receptors (PPAR-
γ) (Lu et al., 2018). Quercetin, found in many plants of Lamiaceae family,
has potent cardioprotective effects by inhibiting the secretion of
adenosine nucleotide from activated platelets and decreasing the
neutrophil function (Kaneider et al., 2004) and reducing the plasma
creatine kinase (CK), cardiac TBARS and NO(x) contents (Ahmed et al.,
2009; Chiş et al., 2018). Another bioactive compound, viz., Carvacrol,
possess cardioprotective activities by suppressing the myocardial
ischemic damage and myocardial enzymes, including cardiac troponin T
(cTnT), creatine kinase (CK) and lactate dehydrogenase (LDH). It
elevates the activities of the antioxidant enzymes superoxide dismutase
(SOD), non-enzymatic scavenger glutathione (GSH), and glutathione
peroxidase (GSH-PX). It has been shown to inhibit the caspase-3
activation and Bax protein expressions but upregulated Bcl-2 protein
expression while reducing the activity of malondialdehyde (Yu et al.,
2013). The cardioprotective effects of carvacrol are through the two
signalling pathways, viz., MAPK/ERK and Akt/eNOS (Chen Y. et al.,
2017). Thymoquinone, one of the active constituents of Thymus plant
species, improves cardiac and reduces infarct size and mediate by a
decrease in cardiac lactate dehydrogenase and creatine kinase levels and
suppressed non-oxidative stress and apoptosis (Xiao et al., 2018). The
cardioprotective effect of thymoquinone is by the up-regulating of SIRT1
expression and inhibition of p53 acetylation (Lu et al., 2018). Baicalein,
an active component found in Scutellaria baicalensis Georgi
and Scutellaria lateriflora L. and other Lamiaceae plants, exhibits
cardioprotective effects besides anti-inflammatory and antioxidant
effects. The activation of MAPK and NF-κB pathways in rats is inhibited,
decreasing MDA level and increasing the SOD and GSH-Px activity
(Kumar et al., 2016; Shi et al., 2018). The compound baicalein, through
the Nrf2/Keap1 pathway, protects cardiomyocytes against oxidative
stress-induced cells (Cui et al., 2015). There are several other bioactive
compounds from plants of Lamiaceae that have similar cardioprotective
properties. Polyphenols display antioxidant effects and vasodilatory
properties (Portincasa and Calamita, 2019) that reduce the
cardiovascular impact. The intake of food rich in flavonoids, and
anthocyanidins reduces the death rate due to cardiovascular diseases
(Portincasa and Calamita, 2019). With advanced awareness on the
benefits of nutraceuticals and plant-derived bioactive molecules for
reducing the risk and incidence of CVDs, the demand for herbal
formulations rich in antioxidants is increasing (Pandey et al., 2010) for
the substitution of synthetic medicines for treating hypertension,
hypercholesterolemia and cardiovascular disease. The stability and
shelf-life of these bioactive compounds during designing for the
prevention of CVDs and tailor-made foods is essential. With the emerging
technologies in the last decade, such as high-pressure homogenization,
pulsed electric fields, and other non-thermal technologies, gas-plasma
were recommended to overcome the nutritional content loss due to the
use of severe thermal treatments (Bekut et al., 2018; Do et al.,
2018; Patrignani et al., 2021).

5.3 Traditional Food Recipe With Lamiaceae

The aromatic Lamiaceae plants rich in phytochemicals have high

antioxidant activity. The introduction of these phytochemicals into the
traditional and modern food recipes has improved the nutritional quality
of the foods (Figure 5). Lamiaceae family attains a significantly higher
figure for cultural importance. This fact remarks the high significance of
the vegetable and herbal tea category in most survey areas (Ali-shtayeh
et al., 2008). Lamiaceae are often used in local cuisines to increase the
digestibility of cooked food. This confirms that the uses of Lamiaceae
plants in food can be relevant to the development of functional foods,
pharmafoods or nutraceuticals as they are aromatic and contain many
essential oils (da Silva et al., 2021). Akshomiya people, during the
celebration of the harvest festival—Bihu, collect 101 plant species and
prepare vegetable recipes in the evening containing four Lamiaceae
species amongst other plants on the first day of the Bohag Bihu, also
called Goru (cow) Bihu (Gogoi and Zaman, 2013). They believe that this
particular recipe has some medicinal values, which is good for health for
the next year too. Barros et al. (2011) have reported that several
traditional recipes are flavoured by seasoning and to preserve food with
the dried leaves and inflorescence of the different species of Lamiaceae
plants. These plants are used in conventional delectable soups and
summer salads. At the last minute, the fresh leaves of ground ivy are
added in different types of soups, viz., soup made of potato, onion and
chopped kale, bean soup, and chickpea-based soups. They are also used
in stewed beans prepared with vegetables and sausages (Barros et al.,
2011). It was reported that the phytochemicals in the refined flour are
much lower since the bran and embryo fractions rich in those
compounds are removed during the milling process as compared to the
whole wheat grains used for the production of the traditional bread
(Skendi et al., 2020b). So, the introduction of phytochemicals from the
Lamiaceae plants will increase the nutritional quality of the final bread
with many health benefits of daily consumption.